Skip to main content

Cardiotoxic Electrophysiological Effects of the Herbicide Roundup® in Rat and Rabbit Ventricular Myocardium In Vitro

Cardiovascular Toxicology volume 15, pages 324–335 (2015)Cite this article

Abstract

Roundup (R), a glyphosate (G)-based herbicide (GBH), containing unknown adjuvants is widely dispersed around the world. Used principally by farmers, intoxications have increasingly been reported. We have studied R effects (containing 36 % of G) on right ventricular tissues (male Sprague–Dawley rats, up to 20,000 ppm and female New Zealand rabbits, at 25 and 50 ppm), to investigate R cardiac electrophysiological actions in vitro. We tested the reduced Ca++ intracellular uptake mechanism as one potential cause of the electrical abnormalities after GBH superfusion, using the Na+/K+-ATPase inhibitor ouabain or the 1,4-dihydropyridine L-type calcium channel agonist BAY K 8644 which increases I Ca. R concentrations were selected based on human blood ranges found after acute intoxication. The study showed dose-dependent V max, APD50 and APD90 variations during 45 min of R superfusion. At the highest concentrations tested, there was a high incidence of conduction blocks, and 30-min washout with normal Tyrode solution did not restore excitability. We also observed an increased incidence of arrhythmias at different doses of R. Ouabain and BAY K 8644 prevented V max decrease, APD90 increase and the cardiac inexcitability induced by R 50 ppm. Glyphosate alone (18 and 180 ppm) had no significant electrophysiological effects. Thus, the action potential prolonging effect of R pointing to I Ca interference might explain both conduction blocks and proarrhythmia in vitro. These mechanisms may well be causative of QT prolongation, atrioventricular conduction blocks and arrhythmias in man after GBH acute intoxications as reported in retrospective hospital records.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Mathur, P. P., & D’Cruz, S. C. (2011). The effect of environmental contaminants on testicular function. Asian Journal of Andrology, 13(4), 585–591. doi:10.1038/aja.2011.40.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  2. Mesnage, R., Bernay, B., & Séralini, G.-E. (2013). Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity. Toxicology, 313(2–3), 122–128. doi:10.1016/j.tox.2012.09.006.

    CAS  Article  PubMed  Google Scholar 

  3. Cavaş, T., & Könen, S. (2007). Detection of cytogenetic and DNA damage in peripheral erythrocytes of goldfish (Carassius auratus) exposed to a glyphosate formulation using the micronucleus test and the comet assay. Mutagenesis, 22(4), 263–268. doi:10.1093/mutage/gem012.

    Article  PubMed  Google Scholar 

  4. Cox, C., & Surgan, M. (2006). Unidentified inert ingredients in pesticides: Implications for human and environmental health. Environmental Health Perspectives, 114(12), 1803–1806.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Monosson, E. (2005). Chemical mixtures: Considering the evolution of toxicology and chemical assessment. Environmental Health Perspectives, 113(4), 383–390.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. Séralini, G.-E., Clair, E., Mesnage, R., Gress, S., Defarge, N., Malatesta, M., & de Vendômois, J. S. (2014). Republished study: Long-term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. Environmental Sciences Europe, 26(1), 14. doi:10.1186/s12302-014-0014-5.

    Article  Google Scholar 

  7. Cassault-Meyer, E., Gress, S., Séralini, G.-É., & Galleraud-Denis, I. (2014). An acute exposure to glyphosate-based herbicide alters aromatase levels in testis and sperm nuclear quality. Environmental Toxicology and Pharmacology, 38, 131–140. doi:10.1016/j.etap.2014.05.007.

  8. Jeyaratnam, J. (1985). Health problems of pesticide usage in the Third World. British Journal of Industrial Medicine, 42(8), 505–506.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Jeyaratnam, J. (1985). 1984 and occupational health in developing countries. Scandinavian Journal of Work, Environment & Health, 11(3 Spec No), 229–234.

    CAS  Article  Google Scholar 

  10. Kim, J., Ko, Y., & Lee, W. J. (2013). Depressive symptoms and severity of acute occupational pesticide poisoning among male farmers. Occupational and Environmental Medicine, 70(5), 303–309. doi:10.1136/oemed-2012-101005.

    Article  PubMed  Google Scholar 

  11. Kim, J., Shin, D.-H., & Lee, W. J. (2014). Suicidal ideation and occupational pesticide exposure among male farmers. Environmental Research, 128, 52–56. doi:10.1016/j.envres.2013.10.007.

    CAS  Article  PubMed  Google Scholar 

  12. Kim, Y. H., Lee, J. H., Hong, C. K., Cho, K. W., Park, Y. H., Kim, Y. W., & Hwang, S. Y. (2013). Heart rate-corrected QT interval predicts mortality in glyphosate-surfactant herbicide-poisoned patients. The American Journal of Emergency Medicine,. doi:10.1016/j.ajem.2013.09.025.

    Google Scholar 

  13. Lee, H. L., Chen, K. W., Chi, C. H., Huang, J. J., & Tsai, L. M. (2000). Clinical presentations and prognostic factors of a glyphosate-surfactant herbicide intoxication: A review of 131 cases. Academic Emergency Medicine, 7(8), 906–910.

    CAS  Article  PubMed  Google Scholar 

  14. Zouaoui, K., Dulaurent, S., Gaulier, J. M., Moesch, C., & Lachâtre, G. (2013). Determination of glyphosate and AMPA in blood and urine from humans: About 13 cases of acute intoxication. Forensic Science International, 226(1–3), e20–e25. doi:10.1016/j.forsciint.2012.12.010.

    CAS  Article  PubMed  Google Scholar 

  15. Jeyaratnam, J. (1990). Acute pesticide poisoning: A major global health problem. World Health Statistics Quarterly. Rapport Trimestriel de Statistiques Sanitaires Mondiales, 43(3), 139–144.

    CAS  PubMed  Google Scholar 

  16. Chan, Y.-C., Chang, S.-C., Hsuan, S.-L., Chien, M.-S., Lee, W.-C., Kang, J.-J., & Liao, J.-W. (2007). Cardiovascular effects of herbicides and formulated adjuvants on isolated rat aorta and heart. Toxicology In Vitro, 21(4), 595–603. doi:10.1016/j.tiv.2006.12.007.

    CAS  Article  PubMed  Google Scholar 

  17. Koyama, K., Koyama, K., & Goto, K. (1997). Cardiovascular effects of a herbicide containing glufosinate and a surfactant: In vitro and in vivo analyses in rats. Toxicology and Applied Pharmacology, 145(2), 409–414. doi:10.1006/taap.1997.8196.

    CAS  Article  PubMed  Google Scholar 

  18. Testud, F., Grillet, J.-P., & Testud, F. (2007). Produits phytosanitaires: Intoxications aiguës et risques professionnels. Paris: Éditions Eska.

    Google Scholar 

  19. Schiariti, M., Puddu, P. E., & Rouet, R. (1994). Multivariate prediction of spontaneous repetitive responses in ventricular myocardium exposed in vitro to simulated ischemic conditions. International Journal of Cardiology, 45(1), 9–22.

    CAS  Article  PubMed  Google Scholar 

  20. De Liz Oliveira Cavalli, V. L., Cattani, D., Heinz Rieg, C. E., Pierozan, P., Zanatta, L., Benedetti Parisotto, E., & Zamoner, A. (2013). Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells. Free Radical Biology and Medicine, 65, 335–346. doi:10.1016/j.freeradbiomed.2013.06.043.

    Article  PubMed  Google Scholar 

  21. Pasdois, P., Quinlan, C. L., Rissa, A., Tariosse, L., Vinassa, B., Costa, A. D. T., & Garlid, K. D. (2007). Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. American Journal of Physiology Heart and Circulatory Physiology, 292(3), H1470–H1478. doi:10.1152/ajpheart.00877.2006.

    CAS  Article  PubMed  Google Scholar 

  22. Bechem, M., & Hoffmann, H. (1993). The molecular mode of action of the Ca agonist (−) BAY K 8644 on the cardiac Ca channel. Pflügers Archiv: European Journal of Physiology, 424(3–4), 343–353.

    CAS  Article  PubMed  Google Scholar 

  23. King-Herbert, A. P., Sills, R. C., & Bucher, J. R. (2010). Commentary: Update on animal models for NTP studies. Toxicologic Pathology, 38(1), 180–181. doi:10.1177/0192623309356450.

    Article  PubMed  Google Scholar 

  24. Puddu, P. E., Legrand, J.-C., Sallé, L., Rouet, R., & Ducroq, J. (2011). I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: Does it really make a difference? Fundamental & Clinical Pharmacology, 25(3), 304–312. doi:10.1111/j.1472-8206.2010.00920.x.

    CAS  Article  Google Scholar 

  25. Rouet, R., Picard, S., Criniti, A., Monti, F., Dawodu, A. A., Ruvolo, G., & Puddu, P. E. (1999). Effects of bimakalim on human cardiac action potentials: Comparison with guinea pig and nicorandil and use-dependent study. Journal of Cardiovascular Pharmacology, 33(2), 255–263.

    CAS  Article  PubMed  Google Scholar 

  26. Cheng, J. (2006). Evidences of the gender-related differences in cardiac repolarization and the underlying mechanisms in different animal species and human. Fundamental & Clinical Pharmacology, 20(1), 1–8. doi:10.1111/j.1472-8206.2005.00384.x.

    CAS  Article  Google Scholar 

  27. Spear, J. F., & Moore, E. N. (2000). Gender and seasonally related differences in myocardial recovery and susceptibility to sotalol-induced arrhythmias in isolated rabbit hearts. Journal of Cardiovascular Electrophysiology, 11(8), 880–887.

    CAS  Article  PubMed  Google Scholar 

  28. Zahradníková, A., Minarovic, I., & Zahradník, I. (2007). Competitive and cooperative effects of Bay K8644 on the L-type calcium channel current inhibition by calcium channel antagonists. The Journal of Pharmacology and Experimental Therapeutics, 322(2), 638–645. doi:10.1124/jpet.107.122176.

    Article  PubMed  Google Scholar 

  29. Séralini, G.-E., Mesnage, R., Defarge, N., Gress, S., Hennequin, D., Clair, E., & de Vendômois, J. S. (2013). Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide. Food and Chemical Toxicology, 53, 476–483. doi:10.1016/j.fct.2012.11.007.

    Article  PubMed  Google Scholar 

  30. Yao, J. A., & Tseng, G. N. (1997). Azimilide (NE-10064) can prolong or shorten the action potential duration in canine ventricular myocytes: Dependence on blockade of K, Ca, and Na channels. Journal of Cardiovascular Electrophysiology, 8(2), 184–198.

    CAS  Article  PubMed  Google Scholar 

  31. Olorunsogo, O. O. (1990). Modification of the transport of protons and Ca2+ ions across mitochondrial coupling membrane by N-(phosphonomethyl)glycine. Toxicology, 61(2), 205–209.

    CAS  Article  PubMed  Google Scholar 

  32. Schoner, W., & Scheiner-Bobis, G. (2007). Endogenous and exogenous cardiac glycosides and their mechanisms of action. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions, 7(3), 173–189.

    CAS  Article  PubMed  Google Scholar 

  33. Saini, H. K., & Dhalla, N. S. (2007). Sarcolemmal cation channels and exchangers modify the increase in intracellular calcium in cardiomyocytes on inhibiting Na+-K+-ATPase. American Journal of Physiology Heart and Circulatory Physiology, 293(1), H169–H181. doi:10.1152/ajpheart.00007.2007.

    CAS  Article  PubMed  Google Scholar 

  34. Hoyer, K., Song, Y., Wang, D., Phan, D., Balschi, J., Ingwall, J. S., & Shryock, J. C. (2011). Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain. The Journal of Pharmacology and Experimental Therapeutics, 337(2), 513–523. doi:10.1124/jpet.110.176776.

    CAS  Article  PubMed  Google Scholar 

  35. Rohr, S., & Kucera, J. P. (1997). Involvement of the calcium inward current in cardiac impulse propagation: Induction of unidirectional conduction block by nifedipine and reversal by Bay K 8644. Biophysical Journal, 72(2 Pt 1), 754–766.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  36. Hondeghem, L. M. (1978). Validity of V max as a measure of the sodium current in cardiac and nervous tissues. Biophysical Journal, 23(1), 147–152. doi:10.1016/S0006-3495(78)85439-3.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  37. Rudy, Y. (2008). Molecular basis of cardiac action potential repolarization. Annals of the New York Academy of Sciences, 1123, 113–118. doi:10.1196/annals.1420.013.

    CAS  Article  PubMed  Google Scholar 

  38. Jouve, R., Langlet, F., Puddu, P. E., Rolland, P. H., Guillen, J. C., Cano, J. P., & Serradimigni, A. (1986). Cicletanide improves outcome after left circumflex coronary artery occlusion-reperfusion in the dog. Journal of Cardiovascular Pharmacology, 8(1), 208–215.

    CAS  Article  PubMed  Google Scholar 

  39. Picard, S., Rouet, R., Ducouret, P., Puddu, P. E., Flais, F., Criniti, A., & Gérard, J. L. (1999). KATP channels and «border zone» arrhythmias: Role of the repolarization dispersion between normal and ischaemic ventricular regions. British Journal of Pharmacology, 127(7), 1687–1695. doi:10.1038/sj.bjp.0702704.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. Li, Q., Lambrechts, M. J., Zhang, Q., Liu, S., Ge, D., Yin, R., & You, Z. (2013). Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis. Drug Design, Development and Therapy, 7, 635–643. doi:10.2147/DDDT.S49197.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Gress, S., Lemoine, S., Séralini, G.-E., & Puddu, P.E. (2014). Glyphosate-based herbicides potently affect cardiovascular system in mammals: Review of the literature. Cardiovascular Toxicology. doi: 10.1007/s12012-014-9282-y.

Download references

Acknowledgments

We wish to thank Josefa de Flores Martos Borrego to her technical help for these experiments. We thank also Nature Vivante and CRIIGEN for fellowship grants to Steeve Gress during the development of his Doctoral Thesis to obtain PhD degree in Molecular and Cellular Biology of the University of Caen Basse-Normandie, France.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Institute of Biology, Risk Pole, MRSH-CNRS, EA 2608 Estrogen, Reproduction and Cancer, University of Caen, Esplanade de la Paix, 14032, Caen Cedex, France

    Steeve Gress & Gilles-Eric Séralini

  2. Institute of Biology, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique, University of Caen, Esplanade de la Paix, 14032, Caen Cedex, France

    Steeve Gress, Sandrine Lemoine & René Rouet

  3. Department of Anesthesiology and Critical Care Medicine, University Hospital of Caen, 14033, Caen Cedex, France

    Sandrine Lemoine

  4. Faculty of Medicine, University of Caen, Caen, France

    Sandrine Lemoine

  5. Laboratory of Biotechnologies Applied to Cardiovascular Medicine, Department of Cardiovascular Sciences, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy

    Paolo-Emilio Puddu

Authors
  1. Steeve Gress
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandrine Lemoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paolo-Emilio Puddu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gilles-Eric Séralini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. René Rouet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo-Emilio Puddu.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gress, S., Lemoine, S., Puddu, PE. et al. Cardiotoxic Electrophysiological Effects of the Herbicide Roundup® in Rat and Rabbit Ventricular Myocardium In Vitro. Cardiovasc Toxicol 15, 324–335 (2015). https://doi.org/10.1007/s12012-014-9299-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-014-9299-2

Keywords

  • Roundup
  • Glyphosate
  • Action potential duration
  • Conduction blocks
  • Pro-arrhythmia
  • Calcium